DESCRIPTION (applicant's abstract): Increasing evidence suggests that psychosocial stress poses a significant health risk. Although it has been documented that many of the effects of physical restraint stress on the immune system are attributable to glucocorticoid-mediated immunosuppression, recent evidence reveals that exposure to a psychosocial stress, social reorganization (SRO), causes increased mortality in an experimental viral infection by novel mechanisms. A salient finding is that peripheral immune cells from SRO animals fail to respond to the suppressive effects of glucocorticoids. Subsequent viral challenge results in hyper-cellular responses and severe tissue damage. However, the mechanisms by which SRO stress induces the observed aberration in glucocorticoid function leading to hyper-cellular and hyper-inflammatory responses have not been determined. The hypothesis to be tested is that the stress of social reorganization induces a state of functional glucocorticoid resistance, resulting in the inability of the host to restrain inflammatory responses. The following specific aims are proposed to test this hypothesis: 1) Examine the social hierarchy and interactions during social reorganization that lead to the development of functional glucocorticoid resistance. 2) Determine how social reorganization alters the regulation of the hypothalamo-pituitary-adrenal axis, which regulates the production of glucocorticoids. 3) Determine the effects of social reorganization on the inflammatory immune responses. 4) Determine the effects of social reorganization on the balance between TH1 and TH2 responses during infection. 5) Determine the cellular mechanisms of GC resistance. Aim 1 is designed to correlate the magnitude and the type of stress with the development of glucocorticoid resistance. In Aim 2, specific changes induced in the neuroendocrine system that translate the state of psychosocial stress to the state of glucocorticoid resistance will be identified. In Aims 3 and 4, we will clarify whether the observed hyper-inflammation is due to an enhanced innate inflammatory response, or due to an inability to switch from a TH1 to a TH2 response, thus prolonging pro-inflammatory responses. Finally, in Aim 5 we will determine whether the function of the glucocorticoid receptors has been altered during social reorganization. This study will attempt to elucidate the central and peripheral mechanisms by which a psychosocial stressor impacts a host's resistance to challenge.